2-cyano alkylbenzomorphan derivatives and salts thereof

ABSTRACT

R7-CH=C(-R8)-   (WHEREIN R7 AND R8 ARE EACH AS DEFINED ABOVE).   (WHEREIN R7 AND R8 ARE EACH AS DEFINED ABOVE AND X IS A HALOGEN ATOM), OR N IS 0 AND A IS A GROUP OF THE FORMULA   X-CH(-R7)-CH(-R8)-   WHEREIN N IS AS DEFINED ABOVE AND A IS A GROUP OF THE FORMULA:   A--CNH2N--CN   WHEREIN R, R1, R2, R3, R4, R5 AND R6 ARE EACH AS DEFINED ABOVE WITH A CYANIDE DERIVATIVES OF THE FORMULA:   2,6-METHANO-3-BENZAZOCINE   1-R3,1-R4,4-R5,6-R1,8-R,9-R6-1,2,3,4,5,6-HEXAHYDRO-   WHEREIN R IS A HYDROGEN ATOM, HYDROXY GROUP, AN ALKOXY GROUP OR AN ACYLOXY GROUP; R1 IS HYDROGEN ATOM, AN ALKYL GROUP, A PHENYL GROUP, A HALOPHENYL GROUP, AN ALKYLPHENYL GROUP, AN ALKOXYPHENYL GROUP, A TRIFLUOROMETHYLPHENYL GROUP, AN ALKOXYPHENYL GROUP OR A GROUP OF THE FORMULA: (CMH2M-P+1)-(R9)P (WHEREIN M IS AN INTEGER OD 1-6, P IS AN INTEGER OF 1-2 AND R9 IS AN ALKOXY GROUP); R2 IS A HYDROGEN ATOM OR AN ALKYL GROUP; R3 IS A HYDROGEN ATOM, AN ALKYL GROUP, A PHENYL GROUP OR AN ALKOXYPHENYL GROUP; R4 IS A HYDROGEN ATOM OR A HYDROXYL GROUP, OR R3 AND R4 MAY FROM AN ALKYLIDENE GROUP OR A CARBONYL GROUP TOGETHER WITH A CARBON ATOM TO WHICH THESE SUBSTITUTENTS ARE BONDED; R5 IS HYDROGEN ATOM OR AN ALKYL GROUP; R6 IS A HYDROGEN ATOM OR A METHYL ATOM GROUP; R7 AND R8 ARE INDEPENDENTLY A HYDROGEN ATOM OR AN ALKYL GROUP; AND N IS AN INTEGER OF 0-2, AND ACID ADDITION SALT THEREOF, WHICH ARE USEFUL AS NON-ADDICTING, ANALGESTIC AND PAIN-RELIEVING AGENTS. THESE BENZOMORPHAN DERIVATIVES ARE PREPARED BY REACTING A 6,7-BENXOMORPHAN DERIVATIVE OF THE FORMULA:   3-BENZAZOCINE   9-R6,11-R2-1,2,3,4,5,6-HEXAHYDRO-2,6-METHANO-   1-R3,1-R4,3-(NC-CNH2N-CH(-R8)-CH(-R7)-),4-R5,6-R1,8-R,   BENZOMORPHAN DERIVATIVES OF THE FORMULA:

United States Patent 3,793,332 Z-CYANO ALKYLBENZOMORPHAN DERIVATIVES ANDSALTS THEREOF Toshio Atsumi, Saitama-ken, Kenji Kobayashi and YoshiakiTakebayashi, Takarazuka, and Hisao Yamamoto, Nishinomiy-a, Japan,assignors to Sumitomo Chemical Company, Limited, Osaka-ski, Japan NoDrawing. Filed May 22, 1972, Ser. No. 255,805 Int. Cl. C07d 39/00 US.Cl. 260-29354 9 Claims ABSTRACT OF THE DISCLOSURE Benzomorphanderivatives of the formula:

R7 Rs wherein R is a hydrogen atom, a hydroxyl group, an alkoxy group oran acyloxy group; R is a hydrogen atom, an alkyl group, a phenyl group,a halophenyl group, an alkylphenyl group, an alkoxyphenyl group, atrifluoromethylphenyl group, an alkylthiophenyl group or a group of theformula: (C H )(R (wherein m is an integer of 1-6, p is an integer of1-2 and R is an alkoxy group); R is a hydrogen atom or an alkyl group; Ris a hydrogen atom, an alkyl group, a phenyl group or an alkoxyphenylgroup; R is a hydrogen atom or a hydroxyl group, or R and R may form analkylidene group or a carbonyl group together with a carbon atom towhich these substituents are bonded; R is a hydrogen atom or an alkylgroup; R is a hydrogen atom or a methyl group; R and R are independentlya hydrogen atom or an alkyl group; and n is an integer of 0-2, and acidaddition salts thereof, which are useful as non-addicting, analgesic andpain-relieving agents. These benzomorphan derivatives are prepared byreacting a 6,7-benzomorphan derivative of the formula:

wherein R, R R R R R and R are each as defined above with a cyanidederivative of the formula:

AC,,H CN

wherein n is as defined above and A is a group of the formula:

B1 Ra (wherein R and R are each as defined above and X is a halogenatom), or n is 0 and A is a group of the formula (wherein R and R areeach as defined above).

The present invention relates to novel Z-cyanoalkylbenzomorphanderivatives and their acid addition salts, which are useful asnon-addicting, analgesic and painrelieving agents, and their productionand compositions containing them.

3,793,332 Patented Feb. 19, 1974 Hitherto, many benzomorphan derivatives(e.g. phenazocine, pentazocine) have been developed as analgesic drugsbut most of them have addiction and produce narcotic symptoms such ascessation of locomotor activity and stupor at their usual dosages. Theproducts of the invention do not show any drug dependency in animaltests.

Accordingly, a main object of the present invention is to providebenzomorphan derivatives which are useful as analgesic andpain-relieving agents without addiction.

The present invention provides a novel 2-cyanoalkyl- 6,7-benzomorphanderivative of the formula:

Jill-H-CJIm-CN R: RI

l [u wherein R is a hydrogen atom, a hydroxyl group, a C -C alkoxy groupor an acyloxy group such as C -C alkanoyloxy; R is a hydrogen atom, a C-C alkyl group, a phenyl group, a halophenyl group, an alkylphenyl group(wherein the alkyl moiety has 1 to 3 carbon atoms), an alkoxyphenylgroup (wherein the alkoxy moiety has 1 to 3 carbon atoms), atrifluoromethylphenyl group, an alkylthiophenyl group (wherein thealkylthio moiety has 1 to 3 carbon atoms) or a group of the formula:

(wherein m is an integer of 1-6, p is an integer of 1-2 and R is a C -Calkoxy group); R is a hydrogen atom or a C -C alkyl group; R is ahydrogen atom, a C -C alkyl group, a phenyl group or an alkoxyphenylgroup (wherein the alkoxy moiety has 1 to 3 carbon atoms); R, is ahydrogen atom or a hydroxyl group, or R and R may form a C -C alkylidenegroup or a carbonyl group together with a carbon atom to which thesesubstituents are bonded; R is a hydrogen atom or a C -C alkyl group; Ris a hydrogen atom or a methyl group; R and R are independently ahydrogen atom or a C -C alkyl group; and n is an integer of 0-2, and itsacid addition salts.

This invention further provides a process for producing the2-cyanoalkyl-6,7-benzomorphan derivative [I], which comprises reacting a6,7-benzomorphan derivative of the formula:

wherein R, R R R R R and R are each as defined above with a cyanidederivative of the formula:

I AC H ,,CN ['III] wherein n is as defined above and A is a group of theformula:

(wherein R and R are each as defined above and X is a halogen atom), orn is 0 and A is a group of the formula:

(wherein R and R are each as defined above).

The invention furthermore provides a novel pharmaceutical compositioncontaining an analgesically effective amount of the2-cyanoalky1-6,7-benzomorphan derivative [I] as an active ingredient anda pharmaceutically acceptable carrier or diluent.

The starting 6,7-benzomorphan derivative [II] is known and can beprepared by demethylating the corresponding 2-methyl-6,7benzomorphanderivative. Thus, for example, United States patent specification No.3,138,- 603 discloses a process shown by the following formulae:

wherein R' is a methoxy group or an acetoxy group.

For the production of the 2-methyl-6,7-benzomorphan derivativerepresented by the formula:

l1 -Rg R 1%, R

wherein R, R R R R R and R are each as defined above, there are knownsome processes, among which a typical process is shown in the followingscheme:

Schemel R2 Ri R Rs 13 Rb N r Y" Ra N Rs I CHa wherein R, R R R R R and Rare each as defined above and Y is a halogen atom. Another typicalprocess is shown in the following scheme:

wherein R, R and R are each as defined above.

The reaction of the 6,7 benzomorphan derivative [II] with the cyanidederivative [111: n: 0-2;

is usually carried out in an inert solvent (e.g. n-hexane, benzene,toluene, xylene, chloroform, dimethylformamide, methanol, ethanol,isopropanol). The presence of a basic substance (e.g. sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumhydroxide, potassium hydroxide, sodium amide, sodium hydride, pyridine,triethylamine) in the reaction is preferred. The reaction proceeds at atemperature of 20 to 200 0, preferably 50 to C. The reaction product isreadily recovered from the reaction mixture by a conventional separationprocedure such as filtration and precipitation.

The reaction of the 6,7-benzomorphan derivative [II] with the cyanidederivative is per se novel and may be called as the modified MichaelAddition. By this reaction, the 2-cyanoalkyl-6,7-benzomorphan derivative[I] can be produced in an excellent yield and a high purity by a simpleoperation. The reaction is carried out in the absence or presence of anappropriate solvent (e.g. methanol, ethanol, ether, chloroform,methylene chloride, benzene, toluene, Xylene, dimethylformamide).Further, there may be used a catalyst, of which examples are Triton B,sodium methoxide, sodium amide, potassium hydroxide, etc. The reactionproceeds at a temperature from about room temperature to the boilingpoint of the solvent employed.

For the production of the 2-cyanoalkyl-6,7-benzomorphan derivative [1:R=acyloxy], the corresponding 2-cyanoalkyl-6,7-benzomorphan derivative[1: R=hydroxyl] may be acylated by a per se conventional procedure, eg.treating with an acid anhydride or acyl halide.

When R is alkyl, the 2-cyanoalkyl-6,7-benzomorphan derivative [I] hastwo stereo isomers, i.e. cis isomer (R being a-configuration) and transisomer (R being ,8- configuration). Each of these isomers can beseparated and purified by a per se conventional procedure such asfractional crystallization, fractional distillation or columnchromatography. Alternatively, each of these isomers may be producedfrom the corresponding cis or trans isomer of the 6,7-benzomorphanderivative [II] by reacting the same with the cyanide derivative [III].Still, each of the said isomers has asymmetric carbon atoms, and therecan be obtained four optically active isomers (i.e. (+)-cis, (-)-cis,(+)-trans, ()-trans) by a conventional optical resolution procedure.

The 2 cyanoalkyl-6,7-benzomorphan derivative [I] possesses a basicnitrogen atom in the fundamental structure and hence various acidaddition salts thereof can be formed. The acid addition salts can beobtained by the use of organic and inorganic acids such as formic acid,acetic acid, propionic acid, butyric acid, malic acid, fumaric acid,succinic acid, glutamic acid, tartaric acid, oxalic acid, citric acid,lactic acid, maleic acid, hydroxymaleic acid, glycolic acid, gluconicacid, glucuronic acid, saccharic acid, ascorbic acid, phenylacetic acid,benzoic acid, p-aminobenzoic acid, phthalic acid, salicylic acid,anthranilic acid, p-hydroxybenzoic acid, p-aminosalicylic acid,picolinic acid, 3-hydroXy-2-naphthoic acid, 3-indolacetic acid, barbituric acid, sulfamic acid, quininic acid, tropic acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,hydroxyethanesulfonic acid, hydrofluoric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid,sulfuric acid, phosphoric acid and the like.

According to the present invention, the following 2-cyanoalkyl-6,7-benzomorphan derivatives [I], and acid addition saltsthereof, can be obtained:

Z-(fl-cyanoethyl)-6,7-benzomorphan2-(fi-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan 2- (fl-cyanoethyl-5-methyl-6,7-benzomorphan 2'-hydroxy-2- (B-cyanoethyl) -6,7-benzomorphan 2'-hydroxy-2-(j3-cyanoethyl)-5-methyl-6,7-benzomorphan2-hydroxy-2- fi-cyano ethyl) -5 ,8 ,9-trimethyl-6,7-benzomorphan2.'-hydroxy-2-(p-cyanoethyl) -3,5-dimethyl-6,7-ben;o-

morphan 2-hydroxy-2-(acyanoethyl -5-phenyl-6,7-benzomorphan2'-hydroxy-2- fi-cyanoethyl -5 ,9- dimethy1-8-oXo-6,7-

benzomorphan 2-hydroxy-3'-methyl-2-(fi-cyanoethyl)-5,9-dimethy1-6,7-

benzomorphan 2'-hydroxy-2-(fi-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan2'-hydroxy-3'-methyl-2-(B-cyanoethyl)-5,9-diethyl-6,7-

benzomorphan 2'-methoxy-2-(fi-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan2'-acetoxy-2-(fl-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan 62'-hydroxy-2- (fl-cyanoethyl -5- (fi-methoxyethyl) -6,7-

benzomorphan 2'-hydroxy-2- (B-cyanoethyl) -5,9-diethyl-6,7-benzomorphan2-hydroxy-2- B-cyanoethyl -5 -methyl-9-ethy1-6,7-

benzomorphan 2'-hydroxy-2-(18-cyanoethyl)-5-ethyl-9-methyl-6,7-

benzomorphan 2'-hydroxy-2- a-methyl-fl-eyanoethyl -5-methyl-6,7-

benzomorphan 2-hydroxy-2- a-methyl-fl-cyanoethyl) -5,9-dimethyl-6,7-benzornorphan 2'-hydroXy-2- B-methyl-p-cyanoethyl) -5-methyl-6,7-

benzomorphan 2'-hydroxy-2- fl-methyl-fl-cyanoethyl) -6 ,9-dimethyl- 6,7-

benzomorphan 2-hydroxy-2- u-ethyl-B-cyanoethyl) -5,9-dimethyl-6,7-

benzomorphan 2'-methoxy-2- a-methyl-fl-cyano ethyl) -5,9-dimethyl-6,7-

benzomorphan 2'-hydroxy-2- ,B-cyano ethyl) -9-methyl-6,7-benzomorphan2'-hydroxy-2- ('y-cyanopropyl) -5,9-dimethyl- 6,7-benzomorphan2'-methoxy-2- 'y-cyanopropyl) -5,9-dimethyl-6,7-b en'zumorphan2'-methoxy-2- B-methyl-'y-cyanopropyl) -5 ,9-dimethyl- 6,7-benzomorphan2'-acetoxy-2- ('y-cyanopropyl -5,9-dimethyl-6,7-benzomorphan2'-acetoxy-2- (B-methyl-y-cyanopropyl -5,9-dimethyl-6,7-

benzomorphan 2-( -cyanopropy1) -5,9-dirnethyl-6,7-benzomorphan2-(fi-methyl-y-cyanopropyl) -5,9-dimethyl-6,7-bei1zomorphan 2-hydroxy-2-('y-cyanopropyl -5-methyl-6,7-benzomorphan 2'-hydroxy-2-('y-cyanopropyl) -9-methyl-6,7-benzomorphan 2-hydroxy-2-(' -cyanopropyl-6,7- benzomorphan '2- 'y-cyan opropyl -5-methyl-6,7-benzo morphan 2-('y-cyanopropyl) -6,7-benzo morphan '-hydroxy-2- ('y-cyanopropyl )-58,9-trimethyl-6,7-

benzomorphan 2'-hydroxy-3 '-methyl-2- 'y-cyanopropyl) -5 ,9-dimethyl- 6,7-b enzomorphan 2'-hydroxy-2- -cyanopropyl -5,9-dimethy1-8-oXo-6,7-

benzomorphan 2.'-hydroxy-2- 'y-cyanopropyl) -3 ,5 -dimethyl-6,7-benzomorphan '-hydroxy-2- ('y-cyanopropyl) -5-phenyl-6,7-benzomorphan2-hydroxy-2- (-y-cyanopropy1) -5- B-methoxyethyl) -6,7-

benzomorphan 2-hydroxy-2- fi-cyanobutyl -5,9-dimethyl-6,7-benzomorphan2'-hydroxy-2- a-cyanobutyl) -6,7-b enzomorphan 2-hydroxy-2-B-cyanobutyl) -5-methyl-6,7benzomorphan -hydroxy-2- a-cyanobutyl) -5,9-dimethyl-8-methylene- 6,7 benzomorphan 2'-hydroxy-3 '-methyl-2-(fi-cyanobutyl) -5,9-dimethyl- 6, 7-benzomor phanZ-(a-cyanobutyI)-6,7-benzomorphan, etc.

6,7-benzomorphan derivatives such as 2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (US. Pat. No. 3,138,603) have a potentanalgesic activity but show an addiction liability. On account of thisaddiction liability, these analgesics are severely restricted in atherapeutic use. Surprisingly, the 2-cyanoalkyl-6,7-benzomorphanderivatives [I] (e.g. 2-hydroxy-2-(fl-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan, 2'-hydroxy-2-(B-cyanoethyU-S-methyl-6,7-benzomorphan,2-acetoxy-2-(B-cyanoethyl)-5,9- dimethy1-6,7-benzomorphan) do not showaddiction in long term animal tests. When, for example, thesecompoundswere administrated orally or subcutaneously to 7 rats everydayfor over one month, the animals did not produce any physical dependencyas shown in Table I.

TABLE I Dose (mg./kg./ Abstiday for nence Compound 4weeks) syndrome2-hydroxy-2- (fl-cyanoethyl) -5, Q-dlmethyl- 20 6, 7-benzomorphan.2-hydroxy-2-(fl-eyanoethyl) -5-methyl-6,7- 20 benzomorphan.2-(Bcyanoethyl)-5-methyl-6,7-benzomorphan--. 20 2 acetoxy-2-(B-cyanoethyl) -5, 9-dimethyl-6, 7- 20 benzomorphan. Mornhinp 202-hydroxy-2, 5, Q-trimethyl-fi,7-benzmorphan.. 20

NorE.-Groups of male rats of Wistar strain (bodyweight, 150 g.), eachgroup consisting of 20 male rats, were subcutaneously given the testcompound twice a day for 4 consecutive weeks. On the next day after drugwithdrawal, the bodyweight was measured. The symbols have the followingmeanings: severe decrease (about decrease); moderate decrease; milddecrease; no decrease. The marked decrease is taken as an indication ofthe possession of a narcotic property by the test compound.

Further, the 2-cyanoalkyl-6,7-benzomorphan derivatives [I] show a stronganalgesic activity. In a subcutaneous writhing test, for instance, theyexhibited much more potent analgesic action than pentazocin (i. e.2'-hydroxy- 2-(3"-methyl-2"-butenyl)-5,9-dimethyl 6,7 benzomorphan),which is one of the strongest, commercial analgesics, as shown in TableII.

TABLE 11 Compound: ED (mg/kg.)

2 hydroxy 2 (fi-cyanoethyl)-5,9-dimethyl- Pentazocine (2' hydroxy 2(3"-methyl-2"- butenyD-5,9-dimethyl-6,7-benzomorphan) 17.5

Note: The test was based on the specific antagonism of the test compoundto the typical syndrome produced by intraperitoneal injection of 0.6%aqueous acetic acid. The syndrome was characterized by intermittentcontractions of the abdomen, twisting and turning of the trunk andextension of the hind legs. A group of 5 mice was used for each doselevel. The test compound was administered subcutaneously 20 minutesbefore the injection of acetic acid. The number of mice which showed nopain response was recorded. The ED value was calculated according to theLitchfeld-Wilcoxons method.

The 2-cyanoalkyl-6,7,-benzomorphan derivatives [I] can be prepared foruse by dissolving under sterile conditions a salt form of them in water(or an equivalent or more amount of a pharmaceutically acceptable acidif the free base is used instead of the salt), or in a physiologicallycompatible aqueous medium such as saline, and stored in ampoules for useby injection. Alternatively, they can be incorporated in unit dosage(1-15 mg.) form as tablets or capsules for oral administration eitheralone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, talc, magnesium stearate and gum acacia.

Practical and presently preferred embodiments of the present inventionare shown in the following examples. Modifications of the proceduresshown in these examples will be obvious to those skilled in the art, andthese examples do not limit the scope of the invention.

8 EXAMPLE 1 2'-hydroxy-2- (fl-cyanoethyl -5,9-dimethyl-6,7- benzomorphanA mixture of 1.1 g. of 2'-hydroxy-5,9-dimethyl-6,7- benzomorphan, 0.5 g.of sodium bicarbonate, 0.42 g. of fi-chloropropionitrile and 20 ml. ofdimethylformamide is stirred at -160 C. for 4 hours. The precipitateproduced is filtered 011. The filtrate is concentrated under reducedpressure to remove the dimethylformamide, and water is added thereto.The precipitate obtained is recrystallized from methanol to yield2'-hydroxy-2-(;8-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan, M.P. 165.5C.

Analysis.-Calcd. for C H N O: C, 75.52; H, 8.20;

N, 10.36%. Found: C, 75.40; H, 8.13; N, 10.31%.

EXAMPLE 2 2'-hydroxy-2- 'y-cyanopropyl) -5,9-dimethyl-6,7-

benzomorphan To a mixture of 1.1 g. of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 0.5 g. of sodium bicarbonate and 20 ml. ofdimethylformamide is added 0.52 g. of 'y-chlorobutyronitrile. v'Iheresultant mixture is stirred at 120-160 C. for 4.5 hours. The solvent isremoved under reduced pressure to leave a residue, to which water isadded. The mixture is extracted with ether, and the extract is washed,dried over anhydrous sodium sulfate and filtered. The filtrate isconcentrated to dryness to give2'-hydroxy-2-('ycyanopropyl)-5,9-dimethyl-6,7-benzomorphan as a viscousliquid.

IR 5331"; 2250, 1670 (weak), 1613, 1585, 1500 T. L. C. (silica gel) Rfvalue: 0.55 (acetone).

EXAMPLE 3 2'-acetoxy-2-'y-cyanopropyl)-5,9-dimethyl-6,7- benzomorphanEXAMPLE 4 2 hydroxy 2 ('y-cyanopropyl) 5 methyl 9 ethyl 6,7-benzomorphanTo a mixture of 0.58 g. of 2'-hydroxy-5-methyl-9-ethy1-6,7-benzomorphan, 0.32. g. of sodium bicarbonate and 15 ml. ofdimethylformamide is added 0.28 g. of 'y-chlorobutyronitrile. Theresultant mixture is refluxed for 4 hours. The precipitate produced isfiltered off. The filtrate is concentrated under reduced pressure toremove the solvent, and Water is added thereto. The precipitate obtainedis recrystallized from ethyl acetate to give2'-hydroxy-2-('ycyanopropyl) 5 methyl-9-ethyl 6,7-benzomorphan, M.P.154-157 C.

IR Vern-1 Analysia- Calcd. for C H N O: C, 76.47; H, 8.78; N, 9.39%.Found: C, 76.73; H, 8.96; N, 9.19%.

' 9 EXAMPLE 2'-hydroxy-2-(6-cyanobutyl)-5,9-dimethyl-6,7- benzomorphanparaifin' 802, 775

Analysis.Calcd. for C H N O: C, 76.47; H, 8.78; N, 9.39%. Found: C,76.31; H, 8.79; N, 9.21%.

EXAMPLE 6 2- fl-cyanoethyl) -5-methyl-6,7-benzomorphan A solution of 1.0g. of S-methyl-6,7-benzomorphan in 20 ml. of absolute ether is addeddropwise to 20 ml. of acrylonitrile at room temperature. The resultantmixture is refluxed for 20 minutes and concentrated to dryness to giveZ-(B-cyanoethyl)-5-methyl-6,7-benzomorphan as a bIOWn oil. This freebase is converted to the hydrochloride by treating withmethanol-hydrochloric acid. The hydrochloride is recrystallized fromacetone-methanol to give Z-(fl-cyanoethyl)-5-methyl-6,7-benzomorphanhydrochlo ride, M.P. 213.5215.0 C.

IR vgg g 2420, 2240 Analysis.-Calcd. for C H N Cl: C, 69.42; H, 7.64; N,10.12; Cl, 12.81%. Found: C, 69.72; H, 7.73; N, 10.10; Cl, 12.16%.

EXAMPLE 7 Z-(fi-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan A mixture of2.01 g. of 5 ,9-dimethyl-6,7-benzomorphan, 40 ml. of absolute ether and0.55 g. of acrylonitrile is refiuxed for one hour and concentrated to ayellow residue, which is distilled under reduced pressure to yield 1.6g. of 2-(;8-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan, B.P. 150-155"C./0.28 mm. Hg.

IR wig": 2230, 14.90

A solution of Z-(B-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan in ether isacidified with gaseous hydrogen chloride. The precipitate produced iscollected by filtration and washed with ether. Recrystallization fromacetone-methanol gives Z-(B-cyanoethyl)-5,9-dimethyl-6,7-benzomorphanhydrochloride, M.P. 238240 C. (decomposition).

IR vggt 2550, 2240, 905, 763, 750, 722

Analysis.-Calcd. for C H N Cl: C, 70.20; H, 7.97; N, 9.63; CI, 12.19%.Found: C, 70.32; H, 7.95; N, 9.84; Cl, 12.34%.

EXAMPLE 8 2'-hydroxy-2- (fi-cyanoethyl) -5-methyl-6,7- benzomorphan To asolution of 1.02 g. of 2'-hydroxy-5-methyl-6,7-benzomorphan in 20 ml. ofmethanol is added 10 ml. of acrylonitrile. The resultant mixture isstirred at room temperature for 2 hours and concentrated to dryness togive crude 2' hydroxy 2 (B cyanoethyl) 5 methyl 6,7 benzomorphan.Recrystallization from ethyl acetate yields 2'-hydroxy-Z-(p-cyanoethyD-S-methyI-G,7-benzomorphan as prisms, M.P.161-163 C.

IR vggg 2600, 2240, 1610, 1580, 1500 Analysis.Calcd. for c H N O: C,74.96; H, 7.86; N, 10.93%. Found: C, 74.66; H, 7.95; N, 10.98%.

10 EXAMPLE 9 2'-acetoxy-Z-(fl-cyanoethyD-5,9-dimethyl-6,7- I

benzomorphan A mixture of 1.0 g. of 2'-hydroxy-2-(,8-cyanoethyl)-5,9-dimethyl-6,7-benzomorphan and 10 ml. of acetic anhydride is stirred at110 C. for one hour, cooled and poured into ice water. The mixture ismade alkaline with aqueous potassium hydroxide (50%) while keeping icecold and extracted quickly with ether. The ether extract is washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate and filtered. 'Ihe filtrate is concentrated to dryness to give2'-acetoxy-2-(]3- cyanoethyl)-5,9-dimethyl-6,7-benzomorphan as a yellowliquid.

IR vffg: 2250, 1755, 1620, 1580, 1492, 1375, 1010, 942

EXAMPLES 10 TO 12 The following compounds are obtained in accordancewith the manner similar to that of Example 1:

2hydroxy-2-('y-cyanopropyl)-5-methyl-6,7-benzomorphan 2hydroxy-'3'-methyl-2-(,8-cyanoethyl)-5,9-dimethyl-6,7-

benzomorphan 2'-hydroxy-2-(-cyanoethyl)-5-phenyl-6,7-benzomorphanEXAMPLES 13 TO 15 The following compounds are obtained in accordancewith the manner similar to that of Example 8:

2' hydroxy-2-(fi-cyanoethyl)-S-methyl-9-ethyl-6,7-benzomorphan 2 hydroxy2 (;8-cyanoethyl) 5 ethyl 9 methyl- 6,7-benzomorphan 2' hydroxy 2S-cyanoethyl) 5,9 diethyl 6,7-

benzomorphan What is claimed is:

1. A benzomorphan derivative of the formula:

Rs I

wherein R is a hydrogen atom, a hydroxyl group, a C -C alkoxy group or C-C alkanoyloxy group; R is a hydrogen atom, a C -C alkyl group, a phenylgroup, a halophenyl group, an alkylphenyl group (wherein the alkylmoiety has 1 to 3 carbon atoms), an alkoxyphenyl group (wherein thealkoxy moiety has 1 to 3 carbon atoms), a trifluoromethylphenyl group,an alkylthiophenyl group (wherein the alkylthio moiety has 1 to 3 carbonatoms) or a group of the formula: (C H )(R (wherein m is an integer of1-6, p is an integer of l-2 and R is a C -C alkoxy group); R is ahydrogen atom or a C -C alkyl group; R is a hydrogen atom, a C -C alkylgroup, a phenyl group or an alkoxyphenyl group (wherein the alkoxymoiety has 1 to 3 carbon atoms); R, is a hydrogen atom or a hydroxylgroup, or R and R may form a C -C alkylidene group or a carbonyl grouptogether with a carbon atom to which these substituents are bonded; R isa hydrogen atom or a C -C alkyl group; R is a hydrogen atom or a methylgroup; R and R are independently a hydrogen atom or a C -C alkyl group;and n is an integer of 0-2, or its acid addition salt.

2. A benzomorphan derivative of the formula:

wherein R is a hydrogen atom, a hydroxyl group, a C -C alkoxy group oran acyloxy group; R is a hydrogen atom, a C -C alkyl group or a phenylgroup; R is a hydrogen atom or a C -C alkyl group; and n is an integerof 2-4, or its acid addition salt.

3. 2-hydroXy-2-(fl-cyanoethyl)-6,7-benzomorphan.

4. 2' hydroxy 2 (fi-cyanoethyl) 5-methyl-6,7- benzomorphan.

5. 2' hydroxy 2 (p-cyanoethyl) 5,9 dimethyl- 6,7-benzomorphan.

6. 2 hydroxy 2 (p-cyanoethyl) 5,9 diethyl-6,7- benzomorphan.

7. 2' acetoxy 2 (/B-cyanoethyl) 5,9 dimethyl- 6,7-benzomorphan.

8. 2 hydroxy 2 -cyanopropyl) 5,9 dimethyl- 6,7-benzomorphan.

9. 2' hydroxy 2 ('y-cyanopropyl) 5 methyl-9- ethyl-6,7-benzomorphan.

References Cited UNITED STATES PATENTS Albertson et a1. 260-29354 HENRYR. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRE I'll'ON Dated February19, 1974 Patent No. 332

Yoshiaki Takebayashi and Inventor(s)Toshi0 Atsumi, Kenji Kobayashi,

' Hisao Yamarnoto tent It is certified that error appears in theabove-identified pa and that said Letters Patent are hereby corrected asshown below:

In Column 1 After line 8, insert Claims priority, application Japan, May21, 1971, 45/348596 application Japan, December 20, 1971,

Signed and sealed this 15th day of August 197 (SEAL) Attest:

McCOY M. GIBSON, JR. C. MARSHALL DANN Commissioner of Patents AttestingOfficer FORM PO-IOSO (IO-69)

